2,2-Difluoro-16-phenoxy-13,14-dihydro-PGA2 analogs

ABSTRACT

2,2-Difluoro prostaglandin E, F.sub.α, F.sub.β, A and B analog are disclosed with intermediates and with processes for making them. These compounds differ from the prostaglandins in that they have two fluoro atoms at the C-2 position in place of the two hydrogen atoms at C-2 in the prostaglandins. These compounds are useful for a variety of pharmacological purposes, including antiulcer, inhibition of platelet aggregation, increase in nasal patency, labor induction at term, and wound healing.

The present application is a divisional application of Ser. No. 552,708,filed Feb. 25, 1975, now issued as U.S. Pat. No. 4,001,300, on Jan. 4,1977.

The present invention relates to prostaglandin analogs for which theessential material constituting a disclosure therefor is incorporated byreference here from U.S. Pat. No. 4,001,300, issued Jan. 4, 1977.

1. A compound of the formula ##STR1## OR A MIXTURE COMPRISING THATCOMPOUND AND THE ENANTIOMER THEREOF, WHEREIN G IS 2 TO 4,INCLUSIVE;Wherein M₁ is ##STR2## or ##STR3## wherein R₇ and R₈ arehydrogen or methyl, with the proviso that one of R₇ or R₈ is methyl onlywhen the other is hydrogen; Wherein T is alkyl of one to 3 carbon atoms,inclusive, fluoro, chloro, trifluoromethyl, or --OR₄ wherein R₄ is alkylof one to 3 carbon atoms, inclusive, and wherein s is zero, one, 2, or3, with the proviso that not more than two T's are other than alkyl;Wherein R₁ is hydrogen, alkyl of one to 12 carbon atoms, inclusive,cycloalkyl of 3 to 10 carbon atoms, inclusive, aralkyl of 7 to 12 carbonatoms, inclusive, phenyl, phenyl substituted with one, 2, or 3 chloro,alkyl of one to 4 carbon atoms, inclusive, or a pharmacologicallyacceptable cation, ##STR4## ##STR5## AND WHEREIN R₅ is hydrogen ormethyl, with the proviso that R₅ is methyl only when R₇ and R₈ are bothhydrogen.
 2. A compound according to claim 1, wherein M₁ is ##STR6## 3.A compound according to claim 2, wherein g is
 2. 4. A compound accordingto claim 3, wherein s is 0 or s is one and T is chloro, fluoro, ortrifluoromethyl.
 5. A compound according to claim 4, wherein R₇ ismethyl.
 6. A compound according to claim 5, wherein s is 1 and T istrifluoromethyl.
 7. 2,2-Difluoro-15 -methyl-16-(m-trifluoromethylphenoxy)-17,18,19,20-tetranor-13,14-dihydro-PGA₁, a compound accordingto claim 6, wherein R₁ is hydrogen. 8.2,2-Difluoro-15-methyl-16-(m-trifluoromethylphenoxy)17,18,19,20-tetranor-13,14-dihydro-PGA₁,methyl ester, a compound according to claim 6, wherein R₁ is methyl. 9.A compound according to claim 5, wherein s is 1 and T is fluoro. 10.2,2-Difluoro-15-methyl-16-(p-fluorophenoxy)-17,18,19,20-tetranor-13,14-dihydro-PGA₁,a compound according to claim 9, wherein R₁ is hydrogen. 11.2,2-Difluoro-15-methyl-16-(p-fluorophenoxy)-17,18,19,20-tetranor-13,14-dihydro-PGA.sub.1,methyl ester, a compound according to claim 9, wherein R₁ is methyl. 12.A compound according to claim 5, wherein s is one and T is chloro. 13.2,2-Difluoro-15-methyl-16-(p-chlorophenoxy)-17,18,19,20-tetranor-13,14-dihydroPGA₁, a compound according to claim 12, wherein R₁ is hydrogen. 14.2,2-Difluoro-15-methyl-16-(p-chlorophenoxy)-17,18,19,20-tetranor-13,14-dihydro-PGA.sub.1,methyl ester, a compound according to claim 12, wherein R₁ is methyl.15. A compound according to claim 5, wherein s is
 0. 16.2,2-Difluoro-15-methyl-16-phenoxy-17,18,19,20-tetranor-13,14-dihydro-PGA₁,a compound according to claim 15, wherein R₁ is hydrogen. 17.2,2-Difluoro-15-methyl-16-phenoxy-17,18,19,20-tetranor-13,14-dihydro-PGA₁,methyl ester, a compound according to claim 15, wherein R₁ is methyl.18. A compound according to claim 4, wherein R₈ is methyl.
 19. Acompound according to claim 18, wherein s is one, and T istrifluoromethyl. 20.2,2-Difluoro-16-(m-trifluoromethylphenoxy)-17,18,19,20-tetranor-13,14-dihydro-PGA₁,15-methyl ether, a compound according to claim 19, wherein R₁ ishydrogen. 21.2,2-Difluoro-16-(m-trifluoromethylphenoxy)-17,18,19,20-tetranor-13,14-dihydro-PGA₁,15-methyl ether, methyl ester, a compound according to claim 19, whereinR₁ is methyl.
 22. A compound according to claim 18, wherein T is fluoro.23.2,2-Difluoro-16-(p-fluorophenoxy)-17,18,19,20-tetranor-13,14-dihydro-PGA₁,15-methyl ether, a compound according to claim 22, wherein R₁ ishydrogen. 24.2,2-Difluoro-16-(p-fluorophenoxy)-17,18,19,20-tetranor-13,14-dihydro-PGA₁,15-methyl ether, methyl ester, a compound according to claim 22, whereinR₁ is methyl.
 25. A compound according to claim 18, wherein s is one andT is chloro. 26.2,2-Difluoro-16-(p-chlorophenoxy)-17,18,19,20-tetranor-13,14-dihydro-PGA₁,15-methyl ether, methyl ester, a compound according to claim 25, whereinR₁ is hydrogen. 27.2,2-Difluoro-16-(p-chlorophenoxy)-17,18,19,20-tetra-13,14-dihydro-PGA₁,15-methyl ether, methyl ester, a compound according to claim 25, whereinR₁ is methyl.
 28. A compound according to claim 18, wherein s is
 0. 29.2,2-Difluoro-16-phenoxy-17,18,19,20-tetranor-13,14-dihydro-PGA₁,15-methyl ether, a compound according to claim 28, wherein R₁ ishydrogen. 30.2,2-Difluoro-16-phenoxy-17,18,19,20-tetranor-13,14-dihydro-PGA₁,15-methyl ether, methyl ester, a compound according to claim 28, whereinR₁ is methyl.
 31. A compound according to claim 4, wherein R₇ and R₈ arehydrogen.
 32. A compound according to claim 31, wherein R₅ is methyl.33. A compound according to claim 32, wherein s is one and T istrifluoromethyl. 34.2,2-Difluoro-16-methyl-16-(m-trifluoromethylphenoxy)-18,19,20-trinor-13,14-dihydro-PGA.sub.1,a compound according to claim 33, wherein R₁ is hydrogen. 35.2,2-Difluoro-16-methyl-16-(m-trifluoromethylphenoxy)-18,19,20-trinor-13,14-dihydro-PGA₁,methyl ester, a compound according to claim 33, wherein R₁ is methyl.36. A compound according to claim 32, wherein s is one and T is fluoro.37.2,2-Difluoro-16-methyl-16-(p-fluorophenoxy)-18,19,20-trinor-13,14-dihydro-PGA₁,a compound according to claim 36, wherein R₁ is hydrogen. 38.2,2-Difluoro-16-methyl-16-(p-fluorophenoxy)-18,19,20-trinor-13,14-dihydro-PGA₁,methyl ester, a compound according to claim 36, wherein R₁ is methyl.39. A compound according to claim 32, wherein s is one and T is chloro.40.2,2-Difluoro-16-methyl-16-(p-chlorophenoxy)-18,19,20-trinor-13,14-dihydro-PGA₁,a compound according to claim 39, wherein R₁ is hydrogen. 41.2,2-Difluoro-16-methyl-16-(p-chlorophenoxy)-18,19,20-trinor-13,14-dihydro-PGA₁,methyl ester, a compound according to claim 39, wherein R₁ is methyl.42. A compound according to claim 32, wherein s is
 0. 43.2,2-Difluoro-16-methyl-16-phenoxy-18,19,20-trinor-13,14-dihydro-PGA₁,methyl ester, a compound according to claim 42, wherein R₁ is methyl.44.2,2-Difluoro-16-methyl-16-phenoxy-18,19,20-trinor-13,14-dihydro-PGA₁,methyl ester, a compound according to claim 42, wherein R₁ is methyl.45. A compound according to claim 31, wherein R₅ is hydrogen.
 46. Acompound according to claim 45, wherein s is one and T istrifluoromethyl. 47.2,2-Difluoro-16-(m-trifluoromethylphenoxy)-17,18,19,20-tetranor-13,14-dihydro-PGA₁,a compound according to claim 46, wherein R₁ is hydrogen. 48.2,2-Difluoro-16-(m-trifluoromethylphenoxy)-17,18,19,20-tetranor-13,14-dihydro-PGA₁,methyl ester, a compound according to claim 46, wherein R₁ is methyl.49. A compound according to claim 45, wherein s is one and T is fluoro.50.2,2-Difluoro-16-(p-fluorophenoxy)-17,18,19,20-tetra-13,14-dihydro-PGA.sub.1,a compound according to claim 49, wherein R₁ is hydrogen. 51.2,2-Difluoro-16-(p-fluorophenoxy)-17,18,19,20-tetranor-13,14-dihydro-PGA₁,methyl ester, a compound according to claim 49, wherein R₁ is methyl.52. A compound according to claim 45, wherein s is one and T is chloro.53.2,2-Difluoro-16-(p-chlorophenoxy)-17,18,19,20-tetranor-13,14-dihydro-PGA₁,a compound according to claim 52, wherein R₁ is hydrogen. 54.2,2-Difluoro-16-(p-chlorophenoxy)-17,18,19,20-tetranor-13,14-dihydro-PGA₁,methyl ester, a compound according to claim 52, wherein R₁ is methyl.55. A compound according to claim 45, wherein s is
 0. 56.2,2-Difluoro-16-phenoxy-17,18,19,20-tetranor-13,14-dihydro-PGA₁, acompound according to claim 55, wherein R₁ is hydrogen. 57.2,2-Difluoro-16-phenoxy-17,18,19,20-tetranor-13,14-dihydro-PGA₁, methylester, a compound according to claim 55, wherein R₁ is methyl.
 58. Thecompound according to claim 1, wherein M₁ is ##STR7##